An Ageless Wonder: Decreasing Cardiac CapZ Prevents Myocardial Decline in Aged Mice
Bibliographic record
Abstract
Ageing populations are a worldwide trend: by 2030 the number of people over 65 years of age will double and this cohort will continue to increase by another 50% by 2050. Age is the primary risk factor for cardiovascular disease with a 22% increase in risk every 5 years after age 65. Mitigating the functional decline of the heart that comes with advanced age will reduce susceptibility to heart failure and prolong lifespans. The actin capping protein ‘CapZ’ is a key regulator of molecular remodeling in ageing skeletal muscle. Whether it plays a similar role in the heart has never been investigated. Our objective was to determine if cardiac CapZ is altered in the hearts of aged mice, and to ascertain the impact of these changes. Wildtype C57Bl6 mice of both sexes were aged to 21 months and cardiac function determined by echocardiography. Left ventricular ejection fraction decreased from 77.2 ± 0.3% to 69.7 ± 0.8% (p<0.05) in male mice at 4 and 21 months of age respectively, whereas female mice showed no significant changes with ageing. Left ventricular fractional shortening showed a similar reduction in aged male mice, declining from 40.2 ± 0.3% to 34.1 ± 0.6% (p<0.05) in male mice aged 4 and 21 months. Again, females maintained fractional shortening with ageing. Immunoblot analysis revealed no differences in cardiac CapZ expression in male myocardial samples between 4 and 21 month old mice. Samples from female hearts, however, showed a significant reduction in CapZ protein levels. To determine if the natural reduction in CapZ protein levels seen in female hearts mitigated the functional decline of ageing, we measured myocardial function of CapZ‐deficient transgenic mice by echocardiography. While female CapZ‐deficient transgenic mice again exhibited no differences in cardiac performance between 4 and 21 month old animals, the functional decline that characterized aged male wildtype mice was significantly alleviated in CapZ‐deficient transgenic mice. It has been proposed that one factor contributing to the age‐dependent decline in cardiac performance is a reduction in beta‐adrenergic reserve. We have previously shown that CapZ influences beta‐adrenergic signaling in the heart. We measured the myocardial response to beta‐adrenergic stimulation of Langendorff‐perfused murine hearts and discovered that aged CapZ‐deficient transgenic mice retain a robust positive inotropic response to myocardial beta‐adrenergic activation, unlike aged wildtype mice. These studies represent the first report showing that decreased cardiac CapZ is an endogenous mechanism by which the hearts of female mice protect themselves against ageing, and demonstrate that reduced cardiac CapZ is sufficient to mitigate the functional decline of advanced age. Support or Funding Information CIHR Catalyst Grant
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".